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Funded Studies

Regulation of Alpha-synucleinopathy by BPOZ-2

BPOZ-2 is an anti-tumor protein that has been reported to stimulate the removal of cancer- related protein aggregates in cancer cells. However, its role has never been explored in Parkinson’s disease (PD) and other neuronal disorders. In PD, a group of neurons located in the midbrain is damaged due to the accumulation of alpha-synuclein proteins. Therefore, we want to study if BPOZ-2 is also involved in the removal of alpha-synuclein aggregates in neurons.

Project Description:             
Our aim is to study the molecular mechanism by which BPOZ-2 inhibits the formation of alpha-synuclein aggregates in neurons. First, we would inject BPOZ-2 or inject a gene inhibiting the function of BPOZ-2 in pre-clinical model midbrain. The models would be injected with the toxin MPTP to generate a PD model. Next, we would study protein-to-protein interactions to evaluate the association between alpha-synuclein and BPOZ-2. We also study if the insertion or inhibition of BPOZ-2 can modify the accumulation of alpha-synuclein in midbrain.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Regulating the removal of excess alpha-synuclein is an important target for the restoration of neuronal health and function in PD. However, until now there is only limited success in this area. If this method is successful, BPOZ-2 therapy could be used to slow or stop Parkinson’s progression.

Anticipated Outcome:          
We anticipate significantly less accumulation of alpha-synuclein with injection of BPOZ-2 and more accumulation of alpha-synuclein when BPOZ-2 inhibitors are introduced. We also believe that activity of parkin, the enzyme responsible for the degradation of toxic proteins related to PD, could be modulated by BPOZ-2.

Final Outcome

Previously, we demonstrated that BPOZ-2 could play a crucial role in the amelioration of alpha-synuclein in the cultured dopaminergic (DA) neurons. Here we report that lentiviral administration of bpoz-2 gene indeed lowers the burden of alpha-synuclein in DA neurons in the nigra of A53T transgenic (A53T-Tg) pre-clinical model. Our detailed immunohistochemical and immunoblot analyses have clearly shown that the overexpression of bpoz-2 dramatically improves both the somatic and neuritic alpha-synuclein pathologies in the nigral DA neurons. Similarly, the specific ablation of bpoz-2 by lentiviral-shRNA fails to ameliorate, but strongly increases the load of monomeric and polymeric forms of alpha-synuclein in the nigral DA neurons of A53T-Tg mice as revealed by different immunological analyses. While investigating the mechanism, our IP analyses revealed that BPOZ-2 could be involved in a protein-protein association with PINK-1 and therefore could stimulate PINK-1-dependent autophagic clearance of alpha-synuclein. Our results have demonstrated that bpoz-2 gene therapy could be prospective in the amelioration of alpha-synucleinopathy in PD and other Lewy body diseases.


  • Avik Roy, PhD

    Chicago, IL United States

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